Opioid receptors belong to the large superfamily of G-protein-coupled receptors, which as a class are of fundamental physiological importance as they mediate the physiological actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly interesting members of this receptor family as they are activated both by endogenously produced opioid peptides and by exogenously administered opiate drugs, which remain among the most effective analgesics known. A major limitation to long-term opiate use is the development of physiological tolerance, a profound decrease in analgesic effect. in addition, long term use of opiates causes physiological dependence, a requirement for continue administration of increasing doses of drug to prevent the development of opiate withdrawal symptoms. Receptor desensitization is thought to play a key role in the development of tolerance and dependence to opiate drugs. multiple mechanisms contribute to desensitization including the rapid internalization of receptors. The structurally homologous delta, mu and kappa opioid receptors differ substantially in their ability to undergo regulatory internalization when activated in the same cells by the same ligand. This type-specificity of receptor internalization provides a basis for understanding how closely homologous opioid receptors differ in their physiological regulation. Furthermore, unlike any other G protein-coupled receptor described to date. structurally distinct opiate drugs and native peptides, all of which activate receptor signaling, have opposing effects on receptor internalization. This agonist-selectivity of receptor internalization may provide important insight into why some opiate drugs produce less physiological tolerance and dependence.